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Cancer mechanisms and therapeutics > Breast cancer 1 + 2 > Flashcards

Breast cancer 1 + 2 Flashcards

1
Q

What are the properties of the mammary gland?

A
  • high capacity for growth and regeneration
  • one of the most cancer-prone organs
  • develops mainly in puberty and pregnancy
  • stroma made up of many different cell types
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2
Q

Mouse models are usually used for breast studies. What are the key differences + similarities to human breasts?

A
  • fattier in mice
  • no terminal ductal-lobular units
  • many similarities in terms of the epithelial cells and lineages
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3
Q

What are TDLU?

A
  • terminal ductal lobular units
  • epithelial structures within the breast that produce milk during lactation
  • type 1 are the least differentiated
  • type 3 are the most differentiated and complex
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4
Q

How do TDLUs change throughout life?

A
  • type 1 seen in young women
  • type 2 in pregnancy and lactation
  • type 3 in older women
  • can expand and regress with the menstrual cycles
  • regress with age as there is less of a need for ovarian hormone receptors in menopause
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5
Q

What cells are the breast epithelium mainly made of?

A
  • basal/myoepithelial outer layer
  • luminal cells
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6
Q

What are the two types of luminal cells?

A
  • hormone receptor positive sensor cells - sense hormones and signal for responders to proliferate
  • hormone receptor negative responder cells
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7
Q

What kinds of cells compose the breast stroma?(4)

A
  • endothelial cells
  • adipocytes
  • fibroblasts
  • immune cells
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8
Q

What are the 6 key stages of mammary gland development?

A
  • fetal
  • puberty
  • estrous cycles
  • pregnancy
  • lactation
  • involution
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9
Q

How does post-natal mammary gland development occur?

A
  • terminal end buds are made first
  • ovarian hormones and growth factors at puberty drive the invasion of epithelial cells and the production of ducts
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10
Q

Mouse models have shown that which proteins are essential for normal mammary gland ductal development? (7)

A
  • GH receptors
  • ER-a
  • IGF-1
  • ovarian and pituitary hormones
  • aromatase (estrogen biosynthesis)
  • amphiregulin (EGF family)
  • other EGF family proteins
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11
Q

How do we know the importance of hormone sensing epithelial cells?

A
  • KO of progesterone receptors in hormone sensing cells
  • leave receptor negative cells alone
  • no growth can occur
  • paracrine factors produced by ER PR positive cells are required for proliferation of negative ones
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12
Q

How does growth hormone contribute to the pubertal mammary gland development?

A
  • secreted by the pituitary gland
  • acts on stromal cells that produce IGF-1
  • IGF-1 binds epithelial cells and triggers cell survival and proliferation
  • liver is also able to develop IGF-1 but is less important
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13
Q

How does estrogen contribute to pubertal mammary gland development?

A
  • secreted by the ovary
  • also induces stromal cells to produce IGF-1
  • cell survival and proliferation through pathways such as PI3-K and MAPK/ERK
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14
Q

Describe the paracrine signalling that happens downstream of estrogen in pubertal mammary gland development

A
  • estrogen binds nuclear receptors in ER+ cells
  • translocates and induces gene expression of paracrine factors that induce effector cells to proliferate, activate stem cells, stimulate growth and remodelling of the matrix
  • this is mediated by aregulin
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15
Q

Describe the molecular process of estrogen mediating ductal elongation

A
  • estrogen activates:
  • stromal IGF or ER-a on sensor cells
  • leads to cleavage of pro-amphiregulin into active amphiregulin
  • this binds to receptors on nearby stromal cells that release FGFs that bind ERa negative cells to drive their proliferation and branching by the MAPK pathway
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16
Q

Which aspects of breast development are each ovarian hormone more important in?

A
  • regulate eachother one is high when the other is low
  • estrogen is more important in the production of terminal end buds and ductal elongation
  • progesterone is also involved in elongation but mostly in side branching seen in lactation and pregnancy
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17
Q

How can progesterone stimulate cells?

A
  • stimulates intrinsic cell proliferation by cyclin D upregulation
  • stimulates paracrine signalling such as Wnt4 can act on basal cells to stimulate matrix remodelling by proteases
  • stimluates RANKL production which can then signal to PR- cells
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18
Q

How does the RANKL pathway work in progesterone signalling?

A
  • ovary produces progesterone
  • binds PR on PR+ cells
  • RANKL is produced and binds RANK receptor on PR- cells
  • can drive cell survival, growth and proliferation by two key mechanisms
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19
Q

What are the two key mechanisms induced by RANK receptor activation?

A
  • production of IKK-a inhibits IKBs and allows NFkB signalling -> proliferation and survival
  • production of ID2 leads to negative regulation of p21 and pushes the cells to proliferate
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20
Q

What are some breast cancer risk factors? (4)

A
  • gender/age (decreases at menopause)
  • obesity worsens risk postmenopause and reduces in childhood
  • ionising radiation exposure especially in puberty
  • genetics - 5-10%
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21
Q

What are some of the most frequent mutations in inherited breast cancers? (3)

A
  • BRCA 1 + 2 (DNA repair)
  • p53 (Li fraumani syndrome)
  • PTEN
  • more
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22
Q

How can reproductive history affect breast cancer risk?

A
  • 60% hormone driven
  • early puberty and late menopause can increase risk
  • HRT use during menupause
  • pregnancy is considered protective especially in younger women
  • breast feeding is protective
  • mamographic density
23
Q

Why does HRT use affect breast cancer risk?

A

increases risk as synthetic hormones are not turned over the same as natrual ones

24
Q

Why does pregnancy protect against breat cancer?

A

decreased levels of IGF-1 in pregnancy means women who are pregnant young spend less time exposed to IGF-1 and progress faster to a ‘safer’ post-pregnancy state

25
Q

Why does mamogrpahic density affect breast cancer risk?

A
  • may increase risk
  • may just be due to higher densities making it harder to spot tumours in scans
26
Q

What are the 5 molecular subtypes of breast cancer?

A
  • luminal A
  • luminal B
  • HER-2 enriched
  • basal like
  • caludin low
  • can be further classified by histology and markers and common mutations are seen within subtypes
27
Q

What breast cancer subtypes are more associated with certain women?

A
  • triple negatives (basal + claudin) are more commonly seen iny younger women and in block women
  • menopause cancer more likely to be luminal
28
Q

What are 3 of the most commonly mutated genes in breast cancer?

A
  • > 10% of mutations are in
  • p53
  • PI3K subunit p110-a
  • GATA3
29
Q

What is the role of GATA3?

A
  • important in luminal cell identitiy
  • positively regulates ER-a expression and function
30
Q

Why might different people with the same cancer type respond to treatment differently?

A
  • lots of variation within subtypes
  • e.g. someone wiht lots of ER+ cancer cells and someone with only a few ER+ cancer cells are both considered ER+
31
Q

What kinds of drugs are used in breast cancer?

A
  • tamoxifen used in strong ER/PR+ cancers
  • no treatments specific for triple negative cancers unless they have BRCA mutations in which case they can be treated with PARP inhibitors
32
Q

What are the BRCA 1 + 2 mutant breast cancers?

A
  • germline mutations that provide a 50-80% lifetime risk
  • BRCA 1 is seen mutated in basal and triple-negative and provides higher risk
  • BRCA-2 has a sporadic distribution
33
Q

What is the role of normal BRCA 1+ 2?

A
  • maintain genomic stability in proliferating cells
  • key roles in homologous recombination of dsDNA breaks
  • mutations lead to defective DNA repair, genomic instability and sensitivity to DNA damage
34
Q

What is the mechanism of BRCA mediated DNA repair?

A
  • double-stranded breaks activate damage sensors that cause the phosphorylation of BRCA 1
  • binds CtIPand resects the break to facilitate repair
  • recruits a comlpex containing BRCA2 that repairs the DNA by RAD51 mediated HR
35
Q

How do PARP inhibitors act against BRCA mutant breast cancers?

A
  • in normal cells PARP inhibitors stop PARP from repairing single stranded breaks leading to dsBreaks which can be repaired by BRCA
  • in mutant cells, BRCA1 + 2 cant fiz these and so the cells with the mutation are killed
36
Q

What happens in HER2 mutated cancers?

A
  • HER2 forms a homodimer or heterodimer with other receptors to activate PI3K and MEK/ERK
  • increased HER2 in mutants means more chances for dimerisation and activation
  • HER2 receptor amplification seen in 10-20% of breast cancers
37
Q

What can be used to treat HER2+ breast cancers?

A
  • monoclonal antibody that binds HER2 and dimerises with it
  • tyrosine kinase inhibitors can also target HER2 but have many side effects due to its role in many cells
38
Q

What are co-regulators in estrogen signalling?

A
  • co-activators or repressors
  • activate or repress ER-a to regulate pathways tightly
39
Q

What are pioneer factors in estrogen signalling?

A
  • interact with ER-a on the DNA to regulate its activity
  • GATA3
  • FOXA1
  • both commonly mutated in PR+ ER+ cancers
  • positively regulate eachother
40
Q

What are the general s=aims for drugs against ERPR+ breast cancers?

A
  • lowering the amount of systemic estrogen in the body
  • or blocking estrogen from attaching to breast cancer cells
41
Q

Give some examplse of drugs against ER/PR+ breast cancers? (4)

A
  • estrogen receptor downregulators
  • can stop estrogen binding to receptors (tamoxifen antagonist)
  • aromatase inhibitors block the production of systemic estrogen - not from the ovary so only useful in menopause
  • luteinizing hormone-releasing agents can be used to shut down the ovaries
42
Q

Why is ER+ breast cancer more frequently targeted for treatment?

A
  • most ER+ are also PR+
  • PR+ inhibitors tend to have worse side effects so more research has gone into ER+
43
Q

Give some examples of PR+ inhibitors used in breast cancer (3)

A
  • selective PR response modulators already used in endometriosis
  • potential role of Wnt inhibitors
  • RANKL antibodies already used to prevent bone degeneration in older women
44
Q

What are the two types of cancer drug resistence?

A
  • intrinsic resistance - lack of response from therapy
  • acquired resistance - disease progression after an initial positive response treatment becomes less effective over time
45
Q

What mechanisms might lead to resistance to HER2 monoclonal antibodies? (3)

A
  • mutations - > receptors don’t have the correct extracellular domain to bind
  • alterations in P13K to no longer require HER2 activation
  • upregulation of other receptor tyrosine kinases (HER3) take its place
46
Q

What are the two types of tumour heterogenetity?

A
  • between tumours
  • within tumours - very hard to treat and classify
47
Q

What 4 factors drive breast tumour heterogenetiy?

A
  • cell of origin
  • cancer cell plasticity
  • genetic evolution / selective pressure
  • tumour microenvironment (stromal cells and their signals)
48
Q

Which progenitors do mammary gland cells come from?

A
  • MSCs in the embryo
  • become luminal progenitors or basasl myoepithelial progenitors
  • maintain themselves after birth
49
Q

How are mouse models usually used to study cancer cells of origin?

A
  • its difficult to go back and figure out which cell caused the cancer
  • easier to specifically mutate cell types and follow what happens
50
Q

What are been found when studying cell of origin in breast cancer?

A
  • appears most breast cancers come from luminal cell progenitors - even those with basal cell markers and morphology
51
Q

What happened in mouse studies targeting PI3K mutations in luminal and basal cells?

A
  • luminal cells caused more aggressive heterogenous tumours than in basal cells
  • basal likely not the cell of origin
  • cell of origin determines tumour phenotype
52
Q

Is cell of origin always the main determinant of tumour phenotype?

A
  • no
  • sometimes oncogene mutation drives it
  • mutations in B-catenin in luminal and basal cells leads to the same tumour morphology regardless of cell of origin
53
Q

What is tuomur cell plasticity?

A
  • the ability of cancer cells to alter their phenotype due to selective pressure or microenvironment
  • for example going from luminal to basal phenotype
  • can even become stem-like
  • underpins tumour cell heterogeneity

Cancer mechanisms and therapeutics (12 decks)

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